[unreadable] A lethal synergism exists between influenza virus and Streptococcus pneumoniae, accounting for excess mortality during influenza epidemics. The recent development of a mouse model recapitulating lethal synergism allows study of potential mechanisms underlying this synergism. The hypothesis that the sialidase activities of the viral and bacterial neuraminidases (NAs) act synergistically to promote adherence and invasion of pneumococcus will be explored. Human viruses of different subtypes and viruses engineered by reverse genetics to have different total NA activities and relative specificities for alpha (2-3) and alpha (2-6) sialic acids will be studied in bacterial adherence assays and in mouse and ferret models of synergism. The concept that differences in excess mortality based on viral subtype can be related to differences in the activity and specificity of the viral NA will be studied by comparison of these results with historical excess mortality related to particular viruses. The utility of viral NA inhibitors for abrogation of synergism will be evaluated. A detailed understanding of the interaction between influenza virus and pneumococcus will provide support for drug and vaccine based interventions aimed at amelioration of human disease and death caused by pneumococcal superinfection following influenza. More broadly, the proposed work addresses evidence that treatment of viral diseases can change the subsequent outcome of bacterial infections. The research proposed is consistent with the purpose of the RFA as it involves an intermicrobial interaction well known to cause significant human mortality, and it makes use of novel technology (reverse genetics for influenza) and novel animal models. [unreadable] [unreadable]